Alpha Lipoic Acid (ALA)

 

• An organosulfur (an organic compound that contains sulfur).

• Potent antioxidant that is both water- and fat-soluble, which means it can work in every cell or tissue in the body.

•  This is unusual when compared to other antioxidants, which are typically either water- or fat-soluble. 

• These antioxidant properties may be linked to benefits such as lower blood sugar, reduced inflammation, improved nerve function, weight loss, and slowed skin aging.

• A coenzyme involved in cellular metabolism and the Krebs cycle, a series of chemical reactions used by mitochondria to transform energy from carbohydrates, fats, and proteins into carbon dioxide and chemical energy in the form of adenosine triphosphate (ATP) (link).

• ALA treatment significantly reduced 

• weight (WMD: -2.29 kg, 95% CI: -2.98, 1.60, P < .01) 

• BMI (WMD: -0.49 kg/m2 , 95% CI:-0.83,-0.15, P = .005)

• In patients diagnosed with metabolic diseases, significantly decreased (link)

• C-reactive protein (CRP) (SMD = − 1.52; 95% CI, − 2.25, − 0.80; P < 0.001), 

• Interlokin-6 (IL-6) (SMD = − 1.96; 95% CI, − 2.60, − 1.32; P < 0.001)

• Tumor necrosis factor alpha levels (TNF-α) (SMD = − 2.62; 95% CI, − 3.70, − 1.55; P < 0.001) 

• In patients with metabolic diseases, significantly decreased 

• fasting glucose (SMD -0.54; 95% CI, -0.89, -0.19; P = 0.003)

• insulin (SMD -1.01; 95% CI, -1.70, -0.31; P = 0.006)

• homeostasis model assessment of insulin resistance (SMD -0.76; 95% CI, -1.15, -0.36; P < 0.001) 

• hemoglobin A1c (SMD -1.22; 95% CI, -2.01, -0.44; P = 0.002)

• triglycerides (SMD -0.58; 95% CI, -1.00, -0.16; P = 0.006)

• total- (SMD -0.64; 95% CI, -1.01, -0.27; P = 0.001)

• low density lipoprotein-cholesterol (SMD -0.44; 95% CI, -0.76, -0.11; P = 0.008).

• Oral dose was 600mg/day was found to provide the optimal risk to benefit ratio in one analysis. 

• Cancer cells:

• Decreased cell viability and proliferation in breast, ovarian, colorectal, and lung cancer cell lines, and was synergistic with chemotherapy. 2-6 

• Decreased cell migration and invasion in thyroid cancer cell lines.

• In prostate cancer cells, ALA did not affect cell proliferation compared with the control.8

• Particularly in combination with other compounds, may improve quality of life and may have some anticancer activity (link).

• Prolonged lifespan in fruit fly [24], but reduced it in progeric mice [25]. 

NMN Resveratrol Trial: Why We Follow David Sinclair Taking Alpha Lipoic Acid (ALA)

https://www.youtube.com/watch?v=hKcVmP5ivMg

Alpha-lipoic acid supplementation significantly reduces the risk of obesity in an updated systematic review and dose response meta-analysis of randomised placebo-controlled clinical trials, 2020

Background: There are numerous trials reported the effect of alpha-lipoic acid (ALA) on obesity measurements; while no summarised dose-response meta-analysis is available to address the effects of dose and duration of ALA supplementation on obesity measurements. We aimed to summarise the results of studies evaluating the effects of ALA supplementation on obesity measurements in a systematic review and dose-response meta-analysis.

Methods and materials: In a systematic search from Scopus, PubMed, Embase, Proquest electronic databases up to January 2020 relevant studies were retrieved. Randomised, placebo-controlled trials investigating the effect of ALA supplementation on obesity measurements including weight, body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) and fat mass (FM) were included. Two class and dose-response meta-analysis were performed to data analysis.

Results: Totally, 18, 21 and 8 studies were included for the meta-analysis of ALA-weight, ALA-BMI, ALA-WC, respectively. In the two-class meta-analysis, ALA treatment significantly reduced weight (WMD: -2.29 kg, 95% CI: -2.98, 1.60, P < .01) and BMI (WMD: -0.49 kg/m2 , 95% CI:-0.83,-0.15, P = .005) but no effect on WC (WMD: -2.57 cm, 95% CI: -8.91, 3.76; P = .426). While the dose-response meta-analysis revealed that the duration of ALA treatment is a significant factor affecting WC reduction (Pnon-linearity = .047). While no evidence of departure from linearity was observed for other variables; moreover, subgrouping also revealed that gender could be an important factor affecting the ALA impact on WC which was significant among women (WMD: -4.099; CI: -7.837, -0.361; P = .032).

Conclusion: According to our finding, ALA treatment significantly reduced BMI, weight in a two-class meta-analysis without evidence of departure from linearity in terms of dose or duration. While the association of ALA treatment on WC is dependent to the duration of the study. Although further trials evaluating the other obesity measurements specially central obesity will be helpful to infer a more reliable result.

The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials, 2018

Objective

This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effect of alpha-lipoic acid (ALA) supplementation on the inflammatory markers among patients with metabolic syndrome (MetS) and related disorders.

Methods

We searched the following databases until November 2017: PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Three reviewers independently assessed study eligibility, extracted data, and evaluated risk of bias of included primary studies. Statistical heterogeneity was assessed using Cochran’s Q test and I-square (I2) statistic. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as the summary effect size.

Results

Eighteen trials out of 912 potential citations were found to be eligible for our meta-analysis. The findings indicated that ALA supplementation significantly decreased C-reactive protein (CRP) (SMD = − 1.52; 95% CI, − 2.25, − 0.80; P < 0.001), interleukin-6 (IL-6) (SMD = − 1.96; 95% CI, − 2.60, − 1.32; P < 0.001), and tumor necrosis factor alpha levels (TNF-α) (SMD = − 2.62; 95% CI, − 3.70, − 1.55; P < 0.001) in patients diagnosed with metabolic diseases.

Conclusion

In summary, the current meta-analysis demonstrated the promising impact of ALA administration on decreasing inflammatory markers such as CRP, IL-6 and TNF-α among patients with MetS and related disorders.

The effects of alpha-lipoic acid supplementation on glucose control and lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials, 2018

Objective: This systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to summarize the effect of alpha-lipoic acid (ALA) supplementation on glycemic control and lipid profiles among patients with metabolic diseases.

Methods: We searched the following databases till October 2017: MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. The relevant data were extracted and assessed for quality of the studies according to the Cochrane risk of bias tool. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Heterogeneity between studies was assessed by the Cochran Q statistic and I-squared tests (I2). Twenty-four studies were included in the meta-analyses.

Results: The findings of this meta-analysis showed that ALA supplementation among patients with metabolic diseases significantly decreased fasting glucose (SMD -0.54; 95% CI, -0.89, -0.19; P = 0.003), insulin (SMD -1.01; 95% CI, -1.70, -0.31; P = 0.006), homeostasis model assessment of insulin resistance (SMD -0.76; 95% CI, -1.15, -0.36; P < 0.001) and hemoglobin A1c (SMD -1.22; 95% CI, -2.01, -0.44; P = 0.002), triglycerides (SMD -0.58; 95% CI, -1.00, -0.16; P = 0.006), total- (SMD -0.64; 95% CI, -1.01, -0.27; P = 0.001), low density lipoprotein-cholesterol (SMD -0.44; 95% CI, -0.76, -0.11; P = 0.008). We found no detrimental effect of ALA supplementation on high density lipoprotein-cholesterol (HDL-cholesterol) levels (SMD 0.57; 95% CI, -0.14, 1.29; P = 0.11).

Conclusions: Overall, the current meta-analysis demonstrated that ALA administration may lead to an improvement in glucose homeostasis parameters and lipid profiles except HDL-cholesterol levels.

Sources/activators of antioxidants (link)

To counter the deleterious effects of free radicals and OS in the organelle, mitochondria also harbor antioxidants including GSH and enzymes, (superoxide dismutase (SOD) and glutathione peroxidase (GPx),) which are present on both sides of their membranes [67]. Antioxidants could be either endogenous or exogenous. The endogenous antioxidants produced mostly in the mitochondria include superoxide dismutase, (SOD), alpha lipoic acid (ALA), Coenzyme Q10 (CoQ10), catalase (CAT), and glutathione peroxidase (Gpx), glutathion (GSH), ferritin, uric acid, bilirubin, metallothioneine, L-carnitine and melatonin [68]. Exogenous antioxidants are acquired from diet such as vitamin E (α-tocopherol) which is present in vegetable oil and wheat germ. Vitamin E can prevent lipid peroxidation of plasma membrane because it is lipid soluble [69]. Other important exogenous antioxidants found in plants (fruits, vegetables, medicinal herbs) include phenolic compounds (phenolic acids, flavonoids, quinones, coumarins, lignans, stilbenes, tannins etc.), nitrogen compounds (alkaloids, amines, betalains), vitamins, and terpenoids (including carotenoids) [70],[71].

Alpha-lipoic acid inhibits TNF-alpha-induced apoptosis in human bone marrow stromal cells

TNF-alpha is an important mediator of bone loss. In the HS-5 hBMSC, TNF-alpha and H2O2 increased intracellular ROS levels and induced cell apoptosis through activation of caspases, JNK and NF-kappaB. alpha-Lipoic acid prevented these changes induced by TNF-alpha and H2O2, suggesting its potential therapeutic applications in attenuating bone loss.

Introduction: Oxidative stress is an important mediator of bone loss. TNF-alpha, which plays a critical role in the bone loss after menopause, has been shown to increase intracellular oxidative stress. Because oxidative stress is associated with cell death, we analyzed the apoptotic effects of TNF-alpha and H2O2 on human bone marrow stromal cells (hBMSCs). We also examined the protective effects of an important biological thiol antioxidant, alpha-lipoic acid (alpha-LA), against TNF-alpha- and H2O2-induced apoptosis.

Materials and methods: Using the HS-5 hBMSC cell line, we tested whether TNF-alpha-induced apoptosis was mediated by the generation of excessive reactive oxygen species (ROS). Apoptosis was determined by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue exclusion assay, quantitation of histone-associated DNA fragments in cytosol, and the activation of caspases. The mechanisms mediating these apoptotic effects were determined by Western blotting and enzyme immunoassay.

Results: Both TNF-alpha and H2O2 increased intracellular ROS levels, reduced total cellular glutathione levels, activated caspases-3, -9, and -8, and enhanced hBMSC apoptosis. The activation of c-jun N-terminal kinase (JNK) and NF-kappaB mediated these apoptotic effects. Pretreatment of cells with alpha-LA prevented these changes induced by TNF-alpha and H2O2.

Conclusions: Our data show that TNF-alpha increases intracellular ROS in hBMSC and that TNF-alpha and H2O2 induce apoptosis in hBMSC through the activation of JNK and NF-kappaB. Our findings also suggest that alpha-LA may have therapeutic applications in halting or attenuating bone loss associated with increased oxidative stress.

ALPHA LIPOIC ACID (ALA) Boosts Performance & Anti Aging 2020

https://www.youtube.com/watch?v=-J_B2BvZHMQ&t=316s

Lipoic Acid Prevents the Changes of Intracellular Lipid Partitioning by Free Fatty Acid (2013)

Background/Aims

It is suggested that the hepatic lipid composition is more important than lipid quantity in the pathogenesis of non-alcoholic steatohepatitis. We examined whether lipoic acid (LA) could alter intrahepatic lipid composition and free cholesterol distribution.

Methods

HepG2 cells were cultured with palmitic acid (PA) with and without LA. Apoptosis, changes of the mitochondrial structure, intracellular lipid partitioning, and reactive oxygen species (ROS) activity were measured.

Results

Free fatty acid (FA) increased apoptosis, and LA co-treatment prevented this lipotoxicity (apoptosis in controls vs PA vs PA+LA, 0.5% vs 19.5% vs 1.6%, p<0.05). LA also restored the intracellular mitochondrial DNA copy number (553±33.8 copies vs 291±14.55 copies vs 421±21.05 copies, p<0.05) and reversed the morphological changes induced by PA. In addition, ROS was increased in response to PA and was decreased in response to LA co-treatment (41,382 relative fluorescence unit [RFU] vs 43,646 RFU vs 41,935 RFU, p<0.05). LA co-treatment increased the monounsaturated and polyunsaturated FA concentrations and decreased the total saturated FA fraction. It also prevented the movement of intracellular free cholesterol from the cell membrane to the cytoplasm.

Conclusions

LA opposes free FA-generated lipotoxicity by altering the intracellular lipid composition and free cholesterol distribution.

Impact of combined therapy with alpha-lipoic and ursodeoxycolic acid on nonalcoholic fatty liver disease: double-blind, randomized clinical trial of efficacy and safety (2012)

Alpha-lipoic acid 400 mg/day plus UDCA 300 mg/day (ALAUDCA) was investigated in patients over a period of 12 months using a randomized, placebo (PLA)-controlled study with four parallel groups. Serum concentration of gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin and platelets (PLT) were measured at the beginning and at the end of the treatment. Moreover, the AST/ALT ratio and the NAFLD fibrosis score were examined.

A total of 120 patients were randomly assigned to the four groups. ALA and UDCA were safe and well tolerated in the oral daily administration only. AST, ALT, GGT (p < 0.001) showed a significant difference between ALAUDCA and other three groups. Besides, NAFLD fibrosis score underlined a significant reduction (p < 0.04) in the ALAUDCA group, while AST/ALT ratio presented a moderate decline (p > 0.05).

ALAUDCA therapy reduced AST, ALT, GGT values and improved NAFLD fibrosis score and AST/ALT ratio, especially in patients who were on a hypocaloric diet. These findings will be useful in patient selection in future clinical trials with ALAUDCA in long-term studies.

Antileukemic effects of piperlongumine and alpha lipoic acid combination on Jurkat, MEC1 and NB4 cells in vitro (2016)

Aim of study: This research indicated to evaluate the effects of piperlongumine (PL), a biologically active alkaloid, and alpha lipoic acid (ALA), a naturally occurring cofactor existed in multienzyme complexes regulating metabolism on leukemia cells. Excessive production of reactive oxygen species (ROS) can lead to oxidative stress, a state that has been observed in several hematopoietic malignancies, including acute and chronic myeloid leukemias. The importance of the association between oxidative stress and malignancy is not currently clear; however, there is evidence that tumor.derived ROS may promote cell survival, migration and metastasis, proliferation and even drug.resistance depending on the origin of the cancer. Increased oxidative stress in leukemic cells may represent a potential therapeutic target, although there are differing opinions on whether therapeutic strategies should aim to antagonize or further promote oxidative stress in leukemic cells.

Materials and methods: The effects of PL alone (5, 15, 30 μM) and in combination (30 μ M) with ALA (200 μ M) on Jurkat, NB4 and MEC1 leukemia cell lines were investigated through MTT, caspase-3 and cyclooxygenase-2 (COX-2) activities.

Results: Inhibition of COX-2 and the induction of caspase.3 cleavage in Nb4 (acute promyelocytic leukemia) cells were found to be significant following PL application and synergistic effects with combination of ALA (inhibition of COX-2 as 23.74% and 3.55-fold increase of caspase-3).

Conclusion: PL and ALA may have a potential value as a therapeutic agent for patients with acute promyelocytic leukemia.

Louis N.

Take one with a meal. This is what I take. Works well. This will dramatically attenuate the glucose spike, and might attenuate some of the other spikes (triglycerides, amino acids, insulin) as well. I have tested this many times with a glucose meter, and it really works well. I take it with every meal.

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features (2023)

• ALA is a natural compound that acts as an antioxidant and pro-oxidant. It exists in two enantiomers - R-ALA and S-ALA. R-ALA is the naturally occurring form that is an essential cofactor for enzyme complexes involved in energy production [16,17].

• ALA/DHLA (dihydrolipoic acid) acts as a scavenger of free radicals and reactive oxygen species. It also regenerates other antioxidants like vitamin C, vitamin E, and glutathione [18,19,24,25,28]. Through its antioxidant effects, ALA may reduce advanced glycation end products implicated in Alzheimer's disease [27].

• ALA increases glucose uptake, especially in muscle and adipose tissue. It does this through: 1) Activating the insulin receptor cascade involving IRS-1, PI3K, and GLUT4 translocation [2,31,32]; 2) Increasing AMPK activity which also stimulates GLUT4 translocation [2,35]; 3) Stimulating expression of mitochondrial proteins and ER chaperones involved in improving insulin signaling [40,42].

• In pancreatic beta cells, ALA prevents oxidative damage and restores insulin secretion reduced by toxins like oleic acid and 2-deoxy-D-ribose [46,47,48,49]. However, ALA alone inhibits glucose-stimulated insulin secretion, possibly by activating AMPK [3,60]. This may protect beta cells from exhaustion [7,61,62].

• In animal and cell studies, ALA improves insulin sensitivity and protects beta cells. However, human trials in diabetes patients show limited effects on HbA1c versus placebo when added to metformin or sulfonylureas [67,68,69,70,71].

• In T2D patients, intravenous ALA acutely increases insulin sensitivity by 50% during glucose clamps [72]. Oral ALA for 1 month improves insulin sensitivity by 27% [73].

• ALA shows benefits in insulin resistance states like polycystic ovary syndrome (PCOS). In obese PCOS women, ALA lowered insulin, glucose, BMI and HOMA-IR [9]. With inositol, ALA improved menstrual abnormalities [94,95].

• For diabetic peripheral neuropathy, ALA 300-600 mg/day reduces symptoms like pain, paraesthesia and muscle atrophy. It improves nerve conduction velocities [108,109,110]. Benefits are greater with lower HbA1c [110].

• Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinemic hypoglycemia induced by ALA in susceptible individuals. The majority of cases are reported in Japan and associated with HLA-DR4 [12]. In Europe, HLA-DRB1*0403 is the predominant allele [15].

• Proposed mechanisms for IAS include ALA fragmentation of insulin, exposing antigens that generate autoantibodies [128]. IAS remits with ALA discontinuation. HLA testing prior to ALA use can identify at-risk individuals.

Efficacy of Alpha-lipoic Acid in The Management of Diabetes Mellitus: A Systematic Review and Meta-analysis (2019)

[Seems to be a big nothing in T2D]